Activation of NLRP3 inflammasome by SARS-CoV-2 (WP4876)

Orf3a from SARS-CoV has been shown to bind TRAF3 and activate the NLRP3 inflammasome. The activation occurs at two points. First, by ubiquinating NF-kB (p105) to stimulate its proteolytic processing into mature NF-kB (p50), which can then go on to promote the transcription of pro-IL-1B together with RELA (p65). And second, by ubiquitinating ASC (PYCARD) in the NLRP3 inflammasome, which leads to its degradtion and the activation of caspase-1 (CASP1) that goes on to catalyze the production of mature IL-1B, leading to a cytokine storm. While Orf3a of SARS-CoV-2 only has 72.7% sequence identity with that of SARS-CoV, the TRAF3 binding motif PxQxS is 100% conserved (https://alexanderpico.github.io/SARS-CoV-2_Alignments/#Orf3a). Chloroquine, a multi-functional antiviral, decreases the production of IL-1B by affecting "the processing of primary transcripts in the nucleus, the transport of processed mRNA to the cytosol, and the degradation of mRNA." (Jang 2006)

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